During protein synthesis in the endoplasmic reticulum (ER), alanyl-transfer RNA (tRNA) synthetase (AlaRS), which is encoded by the Aars1 gene, attaches alanine molecules to their corresponding tRNAs. Deficiencies in AlaRS, and thus the formation of incorrectly translated and misfolded proteins, elicits an unfolded protein response (UPR) and subsequent apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) signalling. Now, Li Li, Lingfei Luo and colleagues use a forward genetic screen to identify an Aars1 mutant zebrafish allele, which results in increased neuronal apoptosis and compromised neurogenesis due to ER stress and UPR induction. Here, the authors characterise the role of the transcription factor nfe2l2b (a paralogue of Nfe2l2, which encodes Nrf2) in this process, which was upregulated in Aars1 mutant neurons. nfe2l2b is regulated by PERK signalling in two ways. First, nfe2l2b is directly phosphorylated by PERK and translocates to the nucleus to upregulate expression of the pro-apoptotic protein p53. Second, nfe2l2b expression levels are regulated by the transcription factor Chop, which is a downstream effector of PERK. Interestingly, Aars1;nfe2l2b double mutants display increased neuronal cell survival and neurogenesis compared with Aars1 alone. These data solidify nfe2l2b as an executor of pro-apoptotic signals in the UPR response and extend our understanding of tRNA synthetase in neurogenesis.
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